Heterocycles play a central role in modern drug design and this is reflected in the fact that they are present within the majority of marketed drugs. Their prevalence in medicine is not unexpected as heterocycles are the core elements of natural bioactive molecules and medicinal chemistry is centred around simulating the biological effects elicited by these privileged scaffolds.

Advances in organic synthesis are critical to the drug discovery process. The breadth of available synthetic methodologies related to heterocycle functionalization represents an almost endless source of innovation for the medicinal chemist. What is interesting however is the bias within the pharmaceutical industry toward relatively few reaction types. But why are certain methodologies favoured and what has been the long term impact?

Numerous reviews and analyses have been published wherein the types of chemical reactions used by the pharmaceutical industry over the past 30-50 years have been assessed and it has been established that of the current, most frequently used synthetic reactions—for example, amide bond formation, Suzuki-Miyaura cross-coupling, S_NAr—none were discovered within the past 20 years.¹ Increase in available commercial reagents, robustness and chemoselectivity has only amplified medicinal chemists’ preference for these reaction types.

The integration of new, ground-breaking methodologies in heterocycle synthesis such as ring-closing metathesis, C–H activation, multi-component reactions, photoredox catalysis etc. has been slow and this reliance on a select few reaction types has resulted in an overpopulation of a small amount of chemical space. Granted, underlying reasons for selected routes in a medicinal chemistry program are complex and the constant pressure to produce, maintain timelines, follow regulations and remain competitive is valid. However, this approach has not necessarily translated into an increase in FDA approved drugs. It’s fair to question whether or not such a practise is fully exploiting the vast toolbox of synthetic methodology available to medicinal chemists which could lead to new, diverse chemical space and new opportunities to tackle issues presently facing the pharmaceutical industry.

In a recently published OBC review as part of the themed collection on Contemporary Synthesis in Drug Discovery, scientists from Pfizer outline recent developments from both industry and academia in heterocycle synthesis and functionalization within the context of drug discovery. The purpose of this and other reviews is to help raise awareness and even popularize novel synthetic methodologies within the pharmaceutical industry. This is likely to be of greater impact in drug discover if more industrial-academic partnerships were to collaborate in the development of novel synthetic approaches toward medicinally relevant heterocycles. Regardless, advancements in synthetic chemistry are intertwined with the development of interesting molecular designs and transformative medicines.

Recent advancements in reaction control and method development strategies have significantly impacted the way in which synthetic chemistry is performed. Arguably, one of the most widely amenable and enabling technologies is continuous flow chemistry, which can offer advantages over batch in terms of cost, reaction efficiency and safety. Its implementation is changing the way in which we think about and conduct chemistry and in some areas has expanded our synthetic capabilities.

As a result, numerous syntheses of commercially and pharmaceutically relevant compounds are being redesigned around flow processes in order to improve efficiency and reproducibility. In addition, the flow reactor configuration can be readily customized to meet specific reaction demands.

These changes are most evident within the pharmaceutical industry where increasing pressure to continually identify and optimize lead compounds has renewed interest in the development of sustainable and cost effective processes for both research and production purposes.¹

A direct example of this comes from Prof. Ian Baxendale’s laboratory at Durham University.² Heterocyclic motifs are prevalent in pharmaceuticals and have constituted one of the largest areas of research in organic chemistry. Through a convenient telescope continuous flow process, ethyl isocyanoacetate—a highly sensitive and reactive compound frequently used as a key building block in heterocycle synthesis—was generated in situ and used to synthesize diverse heterocyclic structures in a convergent manner.

Continuous flow limits issues related to hazardous exothermic processes, reaction scale-up and handling of highly reactive or toxic intermediates, overcoming numerous safety concerns inherent in batch chemistry. Furthermore, flow chemistries have also been combined with additional features such as microwave irradiation, solid-supported reagents or catalysts, photochemistry, inductive heating and electrochemistry, which greatly increase its application in synthetic organic chemistry.^3,4

Significant developments within the last decade indicate that the full potential of flow chemistry has yet to be realized. As with any new up-and-coming technology, there exist limitations that more and more researchers are willing to tackle. This is evident in the prevalence of flow systems now being utilized not only within academic laboratories but also in industrial institutions.

Interesting and innovative examples of synthetic reactions translated to flow systems have recently been published in Organic and Biomolecular Chemistry and can also be found in the joint OBC/ChemComm collection ‘Recent Advances in Flow Synthesis and Continuous Processing’. Select examples are discussed below.

Establishing a multistep continuous flow process is a logical step forward in the development of flow technology. However, genuine applications remain limited due to inherent challenges such as solvent incompatibility, intermediate work-up and dilution effects. Prof. Floris Rutjes and his coworkers at Radboud University have provided a solution to this problem.⁵ They effectively integrated a two-step chemoenzymatic flow synthesis of incompatible reaction steps through the use of an inline liquid-liquid separation module.

Finally, Prof. Bradely Pentelute and his group at the Massachusetts Institute of Technology very recently reported an efficient continuous-flow system for the challenging synthesis of peptides containing perfluoroaromatic molecules in place of labile disulfide bonds.⁷ Application of a rapid flow-based solid-phase peptide synthesis allowed the researchers to circumvent previously encountered problems associated with this chemistry and has resulted in an overall improvement in quality and isolated yield of the peptides.

To find out more see:

¹ Flash chemistry: flow chemistry that cannot be done in batch. J. Yoshida, Y. Takahashi, A. Nagaki, Chem. Commun., 2013, 49, 9896. DOI: 10.1039/C3CC44709J

² Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines. M. Baumann. A. M. Rodriguez Garcia, I. R. Baxendale, Org. Biomol. Chem., 2015, 13, 4231. DOI: 10.1039/C5OB00245A

³ Liquid phase oxidation chemistry in continuous-flow microreactors. H. P. L. Gemoets, Y. Su, M. Shang, V. Hessel, R. Luque, T. Noël, Chem. Soc. Rev., 2016, 45, 83. DOI: 10.1039/C5CS00447K

⁴ Flow chemistry syntheses of natural products. J. C. Pastre, D. L. Browne, S. V. Ley, Chem. Soc. Rev., 2013, 42, 8849. DOI: 10.1039/C3CS60246J

⁵ Chemoenzymatic flow cascade for the synthesis of protected mandelonitrile derivatives. M.M. Delville, K. Koch, J.C.M. van Hest, F.P.J.T. Ruties, Org. Biomol. Chem., 2015, 13, 1634. DOI: 10.1039/C4OB02128B

⁶ A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions. M. V. Rojo, L. Guetzoyan, I. R. Baxendale, Org. Biomol. Chem., 2015, 13, 1768. DOI: 10.1039/C4OB02376E

⁷ A perfluoroaromatic abiotic analog of H2 relaxin enabled by rapid flow-based peptide synthesis. T. Luhmann, S. K. Mong, M. D. Smino, L. Meinel, B. L. Pentelute, Org. Biomol. Chem., 2016, 14, 3345. DOI: 10.1039/C6OB00208K

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.